Signaling pathways in HPV‐associated cancers and therapeutic implications

Abstract

Human papillomaviruses (HPVs) are small double-stranded circular DNA viruses with 8 kb genomes. So far, more than 150 HPVs have been identified, and 12 types of HPVs have been conclusively linked to cancer by the International Agency for Research on Cancer/World Health Organization. Expression of HPV E5, E6 and E7 oncoproteins can alter multiple signaling pathways to cause cancer. In this review, the signaling pathways activated by these oncoproteins are summarized, and targeted therapy against key signaling molecules is described. E6 can inactivate tumor protein 53 and PDZ (post synaptic density protein-drosophila disk large tumor suppressor-zonula occludens-1 proteins) while stimulating phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), Wnt and Notch pathways. E7 can inhibit retinoblastoma protein and stimulate the PI3K/Akt pathway. Both E6 and E7 can deregulate cellular microRNA expression, which can alter cellular signaling pathways. E5 can sensitize epidermal growth factor receptor to epidermal growth factor to increase activation of PI3K/Akt and mitogen-activated protein kinase pathways. E5 can also inhibit the extrinsic apoptotic pathway. These altered signaling pathways could be critical for the initiation and maintenance of HPVassociated cancers. Therefore, targeted therapy against the key signaling molecules has therapeutic implications. Among these, the possibilities of targeting PI3K/Akt, mammalian target of rapamycin, epidermal growth factor receptor and vascular endothelial growth factor have been extensively studied in many cancers. Some inhibitors have been studied in cervical cancer in both animal models and clinical trials. Although the results are promising, further investigation is warranted.

Novel 1, 3-N, O-Spiroheterocyclic compounds inhibit heparanase activity and enhance nedaplatin-induced cytotoxicity in cervical cancer cells

“…Conversely, exogenous HPA can activate this process [21]. HPV E6 and E7 proteins, two main carcinogenic proteins, can cause cellular transformation via their actions on multiple signal transduction pathways [22]. By increasing p53 ubiquitination, HPV E6 reduces the ability of p53 to activate the promotor of HPA, leading to a higher HPA expression [23, 24].…”

“…By increasing p53 ubiquitination, HPV E6 reduces the ability of p53 to activate the promotor of HPA, leading to a higher HPA expression [23, 24]. E6 stabilizes h-TERT mRNA and increases h-TERT expression, thus leading to an increase in telomerase activity [22]. Tang et al .…”

Emerging strategies for targeting PI3K in gynecologic cancer

“…The specific activities of E5, E6, and E7 have been recently reviewed by Chen and colleagues. [58] Recent data in cervical cancer cells lines have demonstrated that activation of the PI3K pathway induces the ubiquitination of PTEN leading to compounded, uncontrolled positive feedback [59]. Given these mechanistic studies pointing to acquired PI3K pathway activation, investigators tested downstream mTOR inhibition and found potent in vivo activity utilizing cell line derived xenografts [60].…”

The anticancer properties of phytochemical extracts from Salvia plants

“…Expression of HPV E5, E6, and E7 oncoproteins can alter multiple signaling pathways to cause cancer. 118 Unfortunately, infection with high-risk HPV, such as 16 and 18, plays a major role in the incidence of cervical cancer. …”